Dibenzoazulene derivatives for treating thrombosis, osteoporosis, arteriosclerosis

ABSTRACT

Compounds of the formula (I) and their physiologically acceptable salts and solvates are useful as integrin-inhibiting substances. They are especially useful in the prophylaxis and treatment of cardiovascular disorders, of thrombosis, cardiac infarction, coronary heart diseases, arteriosclerosis, osteoporosis, in pathological conditions that are caused or propagated by angiogenesis and in tumor therapy.

This application is a 371 of PCT/EP00/02925 filed Apr. 1, 2000.

The invention relates to compounds of the formula I

in which

R¹ is OR⁴, NHR⁴ or NA″₂,

R² is H, Hal, NO₂, NHR⁴, NA″₂, OR⁴, SO₃R⁴, SO₂R⁴ or SR⁴,

R³ is NH₂, H₂N—C(═NH) or H₂N—(C═NH)—NH, where the primary amino groupscan also be provided with conventional amino protective groups, orR⁵—NH—,

R⁴ is H, A, Ar or Aralk,

R⁵ is a mono- or binuclear heterocycle having 1 to 4 N, O and/or Satoms, which can be unsubstituted or mono-, di- or trisubstituted byHal, A″, —CO—A′, OA′, CN, COOA′, CONH₂, NO₂, ═NH or ═O,

A is alkyl having 1-15 C atoms or cycloalkyl having 3-15 C atoms, whichis unsubstituted or mono-, di- or trisubstituted by R⁶, and in whichone, two or three methylene groups can be replaced by N, O and/or S

R⁶ is Hal, NO₂, NHA′, NA″₂, OA′, phenoxy, CO—A′, SO₃A′, CN, NHCOA′,COOA′, CONA′₂ or SO₂A′,

A′ is H or alkyl having 1-6 C atoms,

A″ is alkyl having 1-6 C atoms,

Ar is a mono- or binuclear aromatic ring system, which is unsubstitutedor mono-, di- or trisubstituted by alkyl having 1-6 C atoms and/or anR⁶-substituted mono- or binuclear aromatic ring system having 0, 1, 2, 3or 4 N, O and/or S atoms,

Aralk is aralkylene having 7-14 C atoms, which is unsubstituted ormono-, di- or trisubstituted by R⁶ and in which one, two or threemethylene groups can be replaced by N, O and/or S,

Hal is F, Cl, Br or I,

m, n in each case independently of one another are 0, 1, 2, 3 or 4,

and their physiologically acceptable salts and solvates.

Similar compounds are disclosed, for example, in WO 97/01540.

The invention is based on the object of finding novel compounds havingvaluable properties, in particular those which can be used for theproduction of medicaments.

It has been found that the compounds of the formula I and their saltsand solvates have very valuable pharmacological properties, togetherwith good tolerability. They act especially as integrin inhibitors,where they particularly inhibit the interactions of the α_(v) integrinreceptors with ligands.

The compounds show particular activity in the case of the integrinsα_(v)β₃ and α_(v)β₅. The compounds are very particularly active asadhesion receptor antagonists for the vitronectin receptor α_(v)β₃.

This action can be demonstrated, for example, according to the methodwhich is described by J. W. Smith et al. in J. Biol. Chem. 265,11008-11013 and 12267-12271 (1990). In Curr. Opin. Cell. Biol. 5, 864(1993), B. Felding-Habermann and D. A. Cheresh describe the importanceof the integrins as adhesion receptors for very different phenomena andsyndromes, especially with respect to the vitronectin receptor α_(v)β₃.

The dependence of the formation of angiogenesis on the interactionbetween vascular integrins and extracellular matrix proteins isdescribed by P. C. Brooks, R. A. Clark and D. A. Cheresh in Science 264,569-71 (1994).

The possibility of inhibition of this interaction and thus of theinitiation of apoptosis (programmed cell death) of angiogenic vascularcells by a cyclic peptide is described by P. C. Brooks, A. M.Montgomery, M. Rosenfeld, R. A. Reisfeld, T.-Hu, G. Klier and D. A.Cheresh in Cell 79, 1157-64 (1994).

The experimental proof that the compounds according to the inventionalso prevent the attachment of living cells to the corresponding matrixproteins, and accordingly also the attachment of tumour cells to matrixproteins, can be furnished in a cell adhesion test which is carried outanalogously to the method of F. Mitjans et al., J. Cell Science 108,2825-2838 (1995).

In J. Clin. Invest. 96, 1815-1822 (1995), P. C. Brooks et al. describeα_(v)β₃ antagonists for the control of cancer and for the treatment oftumour-induced angiogenic diseases. The compounds of the formula Iaccording to the invention can therefore be employed as pharmaceuticalactive compounds, in particular for the treatment of oncoses,osteoporosis, osteolytic disorders and for the suppression ofangiogenesis.

Compounds of the formula I which block the interaction of integrinreceptors and ligands, such as, for example, of fibrinogen on thefibrinogen receptor (glycoprotein IIb/IIIa), prevent, as GPIIb/IIIaantagonists, the spread of tumour cells by metastasis. This is confirmedby the following observations: The spread of tumour cells from a localtumour into the vascular system takes place through the formation ofmicroaggregates (microthrombi) by interaction of the tumour cells withblood platelets. The tumour cells are screened by protection in themicroaggregate and are not recognized by the cells of the immune system.The microaggregates can fix themselves to vessel walls, as a result ofwhich further penetration of tumour cells into the tissue isfacilitated. Since the formation of microthrombi by fibrinogen bindingto the fibrinogen receptors is mediated on activated blood platelets,the GPIIa/IIIb antagonists can be regarded as effective metastasisinhibitors.

Besides the binding of fibrinogen, fibronectin and the von Willebrandfactor to the fibrinogen receptor of the blood platelets, compounds ofthe formula I also inhibit the binding of further adhesive proteins,such as vitronectin, collagen and laminin, to the correspondingreceptors on the surface of various cell types. In particular, theyprevent the formation of blood platelet thrombi and can therefore beemployed for the treatment of thromboses, apoplexy, cardiac infarct,inflammation and arteriosclerosis.

The properties of the compounds can also be demonstrated according tomethods which are described in EP-A1-0 462 960. The inhibition offibrinogen binding to the fibrinogen receptor can be detected by themethod which is indicated in EP-A1-0 381 033.

The platelet aggregation-inhibiting action can be demonstrated in vitroaccording to the method of Born (Nature 4832, 927-929, 1962).

The invention accordingly relates to the compounds of the formula Iaccording to claim 1 and their physiologically acceptable salts andsolvates as GPIIb/IIIa antagonists for the control of thromboses,cardiac infarct, coronary heart disorders and arteriosclerosis.

The invention furthermore relates to the compounds of the formula Iaccording to claim 1 and their physiologically acceptable salts andsolvates for the production of a medicament for use as an integrininhibitor.

The invention relates in particular to compounds of the formula Iaccording to claim 1 and their acceptable salts and solvates for theproduction of a medicament for controlling pathologically angiogenicdisorders, tumours, osteoporosis, inflammation and infections.

The compounds of the formula I can be employed as pharmaceutical activecompounds in human and veterinary medicine, for the prophylaxis and/ortherapy of thrombosis, myocardial infarct, arteriosclerosis,inflammation, apoplexy, angina pectoris, oncoses, osteolytic diseasessuch as osteoporosis, pathologically angiogenic diseases such as, forexample, inflammation, ophthalmological diseases, diabetic retinopathy,macular degeneration, myopia, ocular histoplasmosis, rheumatoidarthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis,Crohn's disease, atherosclerosis, psoriasis, restenosis afterangioplasty, viral infection, bacterial infection, fungal infection, inacute kidney failure and in wound healing for assisting the healingprocess.

The compounds of the formula I can be employed as antimicrobially activesubstances in operations where biomaterials, implants, catheters orheart pacemakers are used. They have an antiseptic action here. Theefficacy of the antimicrobial activity can be demonstrated by theprocess described by P. Valentin-Weigund et al., in Infection andImmunity, 2851-2855 (1988).

The invention further relates to a process for the preparation ofcompounds of the formula I according to claim 1, and of their salts andsolvates, characterized in that

a) a compound of the formula I is set free from one of its functionalderivatives by treating with a solvolysing or hydrogenolysing agent, or

b) a radical R¹, R² and/or R³ is converted into another radical R¹, R²and/or R³, by, for example,

i) converting an amino group into a guanidino group by reaction with anamidinating agent,

ii) hydrolysing an ester,

iii) reducing a carboxylic acid to an alcohol,

iv) converting a hydroxyamidine into an amidine by hydrogenation

and/or converting a base or acid of the formula I into one of its salts.

The compounds of the formula I have at least one chiral centre and cantherefore occur in a number of stereoisomeric forms. All these forms(e.g. D and L forms) and their mixtures (e.g. the DL forms) are includedin the formula I.

Also included in the compounds according to the invention are so-calledprodrug derivatives, i.e. compounds of the formula I modified with, forexample, alkyl or acyl groups, sugars or oligopeptides, which arerapidly cleaved in the body to give the active compounds according tothe invention.

Solvates of the compounds are also included in the compounds accordingto the invention. These are understood to be addition compounds with,for example, water (hydrates) or alcohols such as methanol or ethanol.

The abbreviations mentioned above and below stand for:

Ac acetyl BCC tert-butoxycarbonyl CBZ or Z benzyloxycarbonyl DCCIdicyclohexylcarbodiimide DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DMFdimethylformamide DOPA (3,4-dihydroxyphenyl)alanine DPFN3,5-dimethylpyrazole-1-formamidinium nitrate DMAP dimethylaminopyridineEDCI N-ethyl-N,N′-(dimethylaminopropyl)carbodiimide Et ethyl Fmoc9-fluorenylmethoxycarbonyl HOBt 1-hydroxybenzotriazole Me methyl MTBether methyl tert-butyl ether Mtr4-methoxy-2,3,6-trimethylphenylsulfonyl HCNSu N-hydroxysuccinimide Npneopentyl CBn benzyl ester OBut tert-butyl ester Oct octanoyl OMe methylester OEt ethyl ester Orn ornithine POA phenoxyacetyl TBTUO-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium tetra- fluoroborate TFAtrifluoroacetic acid pTSS salt para-toluenesultonic acid salt Trt trityl(triphenylmethyl) Z or CBZ benzyloxycarbonyl

It is true for the whole invention that all radicals which occur anumber of times can be identical or different, i.e. are independent ofone another.

Formula I below

is

or

i.e. formula I includes those compounds of the formulae I′ and I″, whichhave a single or a double bond between C-1 and C-11a.

Alkyl is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl or tert-butyl, in addition also pentyl, 1-, 2- or3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl,1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl,1-ethyl-2-methylpropyl, 1,1,2-, 1,2,2-trimethylpropyl, heptyl, octyl,nonyl or decyl, and also, for example; trifluoromethyl orpentafluoroethyl.

A′ is preferably H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl or hexyl.

A″ is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl or hexyl.

Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, adamantyl or 3-menthyl. Alkylene is preferablymethylene, ethylene, propylene, butylene, pentylene, in addition alsohexylene, heptylene, octylene, nonylene or decylene. Aralk is aralkyleneand is preferably alkylenephenyl and is, for example, preferably benzylor phenethyl.

A is very particularly preferably methyl, ethyl, propyl, isopropyl,butyl or tert-butyl.

CO—A′ is alkanoyl or cycloalkanoyl and is preferably formyl, acetyl,propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl,decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl,pentadecanoyl, hexadecanoyl, heptadecanoyl or octadecanoyl.

Preferred substituents R⁶ for alkyl, Ar, cycloalkyl and Aralk arepreferably, for example, Hal, NO₂, NH₂, NHA″, such as, for example,methylamino, NA″₂, such as, for example, dimethylamino, methoxy,phenoxy, acyl, such as, for example, formyl or acetyl, CN, NHCOA′, suchas, for example, acetamido, COOA′, such as, for example, COOH ormethoxycarbonyl, CONA′₂ or SO₂A′, in particular, for example, F, Cl,hydroxyl, methoxy, ethoxy, amino, dimethylamino, methylthio,methylsulfinyl, methylsulfonyl or phenylsulfonyl.

In the radicals alkyl, alkylene and cycloalkyl, one, two or threemethylene groups in each case can be replaced by N, O and/or S.

Ar—CO is aroyl and is preferably benzoyl or naphthoyl.

Ar is unsubstituted, preferably—as indicated—mono-substituted phenyl,specifically preferably phenyl, o-, m- or p-tolyl, o-, m- orp-ethylphenyl, o-, m- or p-propylphenyl, o-, m,- or p-isopropylphenyl,o-, m- or p-tert-butylphenyl, o-, m- or p-cyanophenyl, o-, m- orp-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-fluorophenyl, o-,m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- orp-methylthiophenyl, o-, m- or p-methylsulfinylphenyl, o-, m- orp-methylsulfonyl-phenyl, o-, m- or p-aminophenyl, o-, m- orp-methyl-aminophenyl, o-, m- or p-dimethylaminophenyl, o-, m- orp-nitrophenyl, further preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-3,4- or 3,5-dichlorophenyl,2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2-chloro-3-methyl-,2-chloro-4-methyl-, 2-chloro-5-methyl-, 2-chloro-6-methyl-,2-methyl-3-chloro-, 2-methyl-4-chloro-, 2-methyl-5-chloro-,2-methyl-6-chloro-, 3-chloro-4-methyl-, 3-chloro-5-methyl- or3-methyl-4-chloro-phenyl, 2-bromo-3-methyl-, 2-bromo-4-methyl-,2-bromo-5-methyl-, 2-bromo-6-methyl-, 2-methyl-3-bromo-,2-methyl-4-bromo-, 2-methyl-5-bromo-, 2-methyl-6-bromo-,3-bromo-4-methyl-, 3-bromo-5-methyl- or 3-methyl-4-bromophenyl, 2,4- or2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 2,3,4-, 2,3,5-, 2,3,6-,2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-tri-tert-butylphenyl,2,5-dimethylphenyl, p-iodophenyl, 4-fluoro-3-chloro-phenyl,4-fluoro-3,5-dimethylphenyl, 2-fluoro-4-bromo-phenyl,2,5-difluoro-4-bromophenyl, 2,4-dichloro-5-methylphenyl,3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl,2-methoxy-5-methylphenyl, 2,4,6-tri-isopropylphenyl, naphthyl,1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, benzothiadiazol-5-yl orbenzoxa-diazol-5-yl. Ar is further preferably 2- or 3-furyl, 2- or3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4-or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5-or 6-pyrimidinyl, furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl,1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4-or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl,1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-,5- or 6-2H-thiopyranyl, 2-, 3- or 4-4-H-thiopyranyl, 3- or4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-,4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-,2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-,4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-,4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl,4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7-or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl.

R⁵ is a mono- or binuclear heterocycle, preferably 2- or 3-furyl, 2- or3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4-or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5-or 6-pyrimidinyl, furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl,1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4-or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl,1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-,5- or 6-2H-thiopyranyl, 2-, 3- or 4-4-H-thiopyranyl, 3- or4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-,4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-,2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-,4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-,4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl,4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7-or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl.

The heterocyclic radicals can also be partially or completelyhydrogenated. R⁵ can thus also be, for example, 2,3-dihydro-2-, -3-, -4-or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5-furyl, tetrahydro-2- or-3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl,2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-,-4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or-4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl,tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or-4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-,2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or-4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3-or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-isoquinolyl.

The heterocyclic rings mentioned can also be mono-, di- ortrisubstituted by Hal, A, —CO—A, OH, CN, COOH, COOA, CONH₂, NO₂, ═NH or═O.

R⁵ is very particularly preferably 1H-imidazol-2-yl,4,5-dihydro-1H-imidazol-2-yl, 5-oxo-4,5-dihydro-1H-imidazol-2-yl,thiazol-2-yl, 1H-benzimidazol-2-yl, 2H-pyrazol-2-yl, 1H-tetrazol-5-yl,2-imino-imidazolidin-4-on-5-yl, 1-alkyl-1,5-dihydroimidazol-4-on-2-yl,pyridin-2-yl, pyrimidin-2-yl or 1,4,5,6-tetrahydro-pyrimidin-2-yl.

R¹ is particularly, for example, carboxyl, methoxycarbonyl,ethoxycarbonyl, CONH₂, CONHMe, CONHEt, CONMe₂ or CONEt₂. R¹ is veryparticularly preferably carboxyl or ethoxycarbonyl.

R² is preferably, for example, H, Hal, methylsulfonyl, ethylsulfonyl,propylsulfonyl, butylsulfonyl, iso-butylsulfonyl,2,2-dimethylpropylsulfonyl, phenyl-sulfonyl or benzylsulfonyl. R² isvery-particularly preferably H.

R³ is preferably, for example, H₂N—C(═NH), H₂N—(C═NH)—NH,1H-imidazol-2-ylamino, 4,5-dihydro-1H-imidazol-2-ylamino,5-oxo-4,5-dihydro-1H-imidazol-2-ylamino, 1H-benzimidazol-2-ylamino,2H-pyrazol-2-ylamino, 2-imino-imidazolidin-4-on-5-ylamino,1-methyl-1,5-dihydro-imidazol-4-on-2-ylamino, pyridin-2-ylamino,pyrimidin-2-ylamino or 1,4,5,6-tetrahydropyrimidin-2-ylamino.

Accordingly, the invention relates in particular to those compounds ofthe formula I in which at least one of the radicals mentioned has one ofthe preferred meanings indicated above. Some preferred groups ofcompounds can be expressed by the following subformulae Ia to Ih, whichcorrespond to the formula I and in which the radicals not described ingreater detail have the meaning indicated in the formula I, but in which

in Ia) R² is H; in Ib) R² is H and R¹ is COOH or COOA; in Ic) R² is H,R¹ is COOH or COOA and R³ is H₂N—C(═NH), H₂N—(C═NH)—NH, 1H-imidazol-2-ylamino, 4,5-dihydro-1H-imidazol-2-ylamino, 5-oxo-4, 5-dihydro-1H-imidazol-2-ylamino, 1H-benzimidazol-2- ylamino,2H-pyrazol-2-ylamino, 2-iminoimidazolidin-4- on-5-ylamino, 1-methyl-1,5-dihydroimidazol-4-on-2-yl- amino, pyridin-2-ylamino,pyrimidin-2-ylamino or 1,4,5,6- tetrahydro-pyrimidin-2-ylamino; in Id) mis 0 or 1; in Ie) m is 0 or 1 and R² is H; in If) R² is H; R¹ is COOH orCOOA and m is 0 or 1; in Ig) R² is H, R¹ is COOH or COOA and A ismethyl, ethyl, propyl, isopropyl, butyl or tert-butyl and m is 0 or 1;in Ih) R² is H, R¹ is COOH or COOA, A is methyl, ethyl, propyl,isopropyl, butyl or tert-butyl, R³ is H₂N—C(═NH), H₂N—(C═NH)—NH, 1H-imidazol-2-ylamino, 4,5-dihydro-1H-imidazol-2-ylamino, 5-oxo-4,5-dihydro-1H-imidazol-2-ylamino, 1H- benzimidazol-2-ylamino,2H-pyrazol-2-ylamino, 2- iminoimidazolidin-4-on-5-ylamino, 1-metnyl-1,5-dihydroimidazol-4-on-2-ylamino, pyridin-2 -ylamino, pyrimidin-2-ylaminoor 1,4,5,6-tetrahydropyrimidin- 2-ylamino; m is 0 or 1 and n is 2, 3 or4;

and their physiologically acceptable salts and solvates.

Particularly preferred groups of compounds are those below having theformulae indicated in each case

Ia′)

R² is H.

R¹ is COOH or COOA,

A is methyl, ethyl, propyl, isopropyl, butyl or tert-butyl,

R³ is H₂N—C(═NH), H₂N—(C═NH)—NH, 1H-imidazol-2-ylamino,4,5-dihydro-1H-imidazol-2-ylamino,5-oxo-4,5-dihydro-1H-imidazol-2-ylamino, 1H-benzimidazol-2-ylamino,2H-pyrazol-2-ylamino, 2-iminoimidazolidin-4-on-5-ylamino,1-methyl-1,5-dihydroimidazol-4-on-2-ylamino, pyridin-2-ylamino,pyrimidin-2-ylamino or 1,4,5,6-tetrahydropyrimidin-2-ylamino;

m is 0 or 1 and

n is 2, 3 or 4;

Ia″)

R² is H,

R¹ is COOH or COOA,

A is methyl, ethyl, propyl, isopropyl, butyl or tert-butyl,

R³ is H₂N—C(═NH), H₂N—(C═NH)—NH, 1H-imidazol-2-ylamino,4,5-dihydro-1H-imidazol-2-ylamino,5-oxo-4,5-dihydro-1H-imidazol-2-ylamino, 1H-benzimidazol-2-ylamino,2H-pyrazol-2-ylamino, 2-iminoimidazolidin-4-on-5-ylamino,1-methyl-1,5-dihydroimidazol-4-on-2-ylamino, pyridin-2-ylamino,pyrimidin-2-ylamino or 1,4,5,6-tetrahydropyrimidin-2-ylamino;

m is 0 or 1 and

n is 2, 3 or 4;

and their physiologically acceptable salts and solvates.

The compounds of the formula I and also the starting substances fortheir preparation are otherwise prepared by methods known per se, suchas are described in the literature (e.g. in the standard works such asHouben-Weyl, Methoden der organischen Chemie (Methods of OrganicChemistry, Georg-Thieme-Verlag, Stuttgart), namely under reactionconditions which are known and suitable for the reactions mentioned. Usecan also be made in this case of variants which are known per se, butnot mentioned here in greater detail.

If desired, the starting substances can also be formed in situ such thatthey are not isolated from the reaction mixture, but immediately reactedfurther to give the compounds of the formula I.

Compounds of the formula I can preferably be obtained by setting freecompounds of the formula I from one of their functional derivatives bytreating with a solvolysing or hydrogenolysing agent.

Preferred starting substances for the solvolysis or hydrogenolysis arethose which otherwise correspond to the formula I, but instead of one ormore free amino and/or hydroxyl groups contain corresponding protectedamino and/or hydroxyl groups, preferably those which instead of an Hatom which is bonded to an N atom carry an amino protective group, inparticular those which instead of an HN group carry an R′—N-group, inwhich R′ is an amino protected group, and/or those which instead of theH atom of a hydroxyl group carry a hydroxyl protective group, e.g. thosewhich correspond to the formula I, but instead of a group —COOH carry agroup —COOR″, in which R″ is a hydroxyl protective group. It is alsopossible for a number of—identical or different—protected amino and/orhydroxyl groups to be present in the molecule of the starting substance.If the protective groups present are different from one another, in manycases they can be removed selectively.

The expression “amino protective group” is generally known and relatesto groups which are suitable for protecting (for blocking) an aminogroup from chemical reactions, but which are easily removable after thedesired chemical reaction has been carried out at other positions in themolecule. Typical groups of this type are, in particular, unsubstitutedor substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since theamino protected groups are removed after the desired reaction (orreaction sequence), their nature and size is otherwise not critical;however, those having 1-20, in particular. 1-8, C atoms are preferred.The expression “acyl group” is to be interpreted in the widest sense inconnection with the present process. It includes acyl groups derivedfrom aliphatic, araliphatic, aromatic or heterocyclic carboxylic acidsor sulfonic acids, in particular alkoxycarbonyl, aryloxycarbonyl andespecially aralkoxycarbonyl groups. Examples of acyl groups of this typeare alkanoyl such as acetyl, propionyl, butyryl; aralkanoyl such asphenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such asPOA; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl,aralkyloxycarbonyl such as CBZ (“carbobenzoxy”),4-methoxybenzyloxycarbonyl, FMOC; arylsulfonyl such as Mtr. Preferredamino protective groups are BOC and Mtr, in addition CBZ, Fmoc, benzyland acetyl.

The removal of the amino protective group—depending on the protectivegroup used—takes place, for example, using strong acids, expedientlyusing TFA or perchloric acid, but also with other strong inorganic acidssuch as hydrochloric acid or sulfuric acid, strong organic carboxylicacids such as trichloroacetic acid or sulfonic acids such as benzene- orp-toluenesulfonic acid. The presence of an additional inert solvent spossible, but not always necessary. Suitable inert solvents arepreferably organic, for example carboxylic acids such as acetic acid,ethers such as tetrahydrofuran or dioxane, amides such as DMF,halogenated hydrocarbons such as dichloromethane, in addition alsoalcohols such as methanol, ethanol or isopropanol, and also water.Mixtures of the abovementioned solvents are additionally suitable. TFAis preferably used in an excess without addition of a further solvent,perchloric acid in the form of a mixture of acetic acid and 70%perchloric acid in the ratio 9:1. The reaction temperatures for thecleavage are expediently between approximately 0 and approximately 50°;the reaction is preferably carried out between 15 and 30° (roomtemperature).

The groups BOC, OBut and Mtr can preferably be removed, for example,using TFA in dichloromethane or using approximately 3 to 5N HCl indioxane at 15-30°, the FMOC group using an approximately 5 to 50%solution of dimethylamine, diethylamine or piperidine in DMF at 15-30°.

Hydrogenolytically removable protective groups (e.g. CBZ or benzyl) canbe removed, for example, by treating with hydrogen in the presence of acatalyst (e.g. of a noble metal catalyst such as palladium, expedientlyon a support such as carbon). Suitable solvents here are those indicatedabove, in particular, for example, alcohols such as methanol or ethanolor amides such as DMF. As a rule, the hydrogenolysis is carried out attemperatures between approximately 0 and 100° and pressures betweenapproximately 1 and 200 bar, preferably at 20-30° and 1-10 bar.Hydrogenolysis of the CBZ group takes place readily, for example, on 5to 10% Pd/C in methanol or using ammonium formate (instead of hydrogen)on Pd/C in methanol/DMF at 20-30°.

Suitable inert solvents are, for example, hydrocarbons such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbonssuch as trichloro-ethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers such as ethylene glycol monomethyl or monoethyl ether(methyl glycol or ethyl glycol), ethylene glycol dimethyl ether(diglyme); ketones such as acetone or butanone; amides such asacetamide, dimethylacetamide or dimethylformamide (DMF); nitriles suchas acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); carbondisulfide; carboxylic acids such as formic acid or acetic acid; nitrocompounds such as nitromethane or nitrobenzene; esters such as ethylacetate, water or mixtures of the solvents mentioned.

It is additionally possible to convert a radical R¹, R² and/or R³ intoanother radical R¹, R² and/or R³. In particular, a carboxylic acid estercan be converted into a carboxylic acid. Thus it is possible tohydrolyse an ester of the formula I. Expediently, this is carried out bysolvolysis or hydrogenolysis, as indicated above, e.g. using NaOH or KOHin dioxane/water at temperatures between 0 and 60° C., preferablybetween 10 and 40° C.

The conversion of a cyano group into an amidino group is carried out byreaction with, for example, hydroxylamine and subsequent reduction ofthe N-hydroxyamidine with hydrogen in the presence of a catalyst suchas, for example, Pd/C.

It is additionally possible to replace a conventional amino protectivegroup by hydrogen by removing the protective group solvolytically orhydrogenolytically, as described above, or by setting free an aminogroup protected by a conventional protective group by solvolysis orhydrogenolysis.

For the preparation of compounds of the formula I in which R³ isH₂N—C(═NH)—NH—, an appropriate amino compound can be treated with anamidinating agent. The preferred amidinating agent is1-amidino-3,5-dimethylpyrazole (DPFN), which is employed in particularin the form of its nitrate. The reaction is expediently carried out withaddition of a base such as triethylamine or ethyldiisopropylamine in aninert solvent or solvent mixture, e.g. water/dioxane at temperaturesbetween 0 and 120° C., preferably between 60 and 120° C.

For the preparation of an amidine of the formula I (R³=—C(═NH)—NH₂),ammonia can be added to a nitrile of the formula I (R³=CN). The additionis preferably carried out in multi-stage form, in a manner known per se,by a) converting the nitrile with H₂S into a thioamide, which isconverted with an alkylating agent, e.g. CH₃I, into the correspondingS-alkylimido thioester, which for its part reacts with NH₃ to give theamidine, b) converting the nitrile with an alcohol, e.g. ethanol, in thepresence of HCl into the corresponding imido ester and treating thiswith ammonia, or c) reacting the nitrile with lithiumbis(trimethylsilyl)amide and then hydrolysing the product.

Free amino groups can additionally be acylated in a customary mannerusing an acid chloride or anhydride or alkylated using an unsubstitutedor substituted alkyl halide, expediently in an inert solvent such asdichloromethane or THF and/or in the presence of a base such astriethylamine or pyridine at temperatures between −60 and +300.

A base of the formula I can be converted into the associated acidaddition salt using an acid, for example by reaction or equivalentamounts of the base and of the acid in an inert solvent such as ethanoland subsequent evaporation. Suitable acids for this reaction are inparticular those which yield physiologically acceptable salts. Thusinorganic acids can be used, e.g. sulfuric acid, nitric acid, hydrohalicacids such as hydrochloric acid or hydrobromic acid, phosphoric acidssuch as orthophosphoric acid, sulfamic acid, in addition organic acids,in particular aliphatic, alicyclic, araliphatic, aromatic orheterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids,e.g. formic acid, acetic acid, propionic acid, pivalic acid,diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaricacid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid,gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid,methane- or ethanesulfonic acid, ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, naphthalenemono- and disulfonic acids and laurylsulfuric acid.Salts with physiologically unacceptable acids, e.g. picrates, can beused for the isolation and/or purification of the compounds of theformula I.

On the other hand, an acid of the formula I can be converted into one ofits physiologically acceptable metal or ammonium salts by reaction witha base. Possible salts here are in particular the sodium, potassium,magnesium, calcium and ammonium salts in addition substituted ammoniumsalts, e.g. the dimethyl-, diethyl- or diisopropylammonium salts,monoethanol-, diethanol- or diisopropanolammonium salts,-cyclohexyl- ordicyclohexylammonium salts, dibenzyl-ethylenediammonium salts,furthermore, for example, salts with arginine or lysine.

The compounds of the formula I contain one or more chiral centres andcan therefore be present in racemic or in optically active form.Racemates obtained can be resolved into the enantiomers mechanically orchemically by methods known per se. Preferably, diastereomers are formedfrom the racemic mixture by reaction with an optically active resolvingagent. Suitable resolving agents are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such asβ-camphorsulfonic acid. Separation of enantiomers with the aid of acolumn packed with an optically active resolving agent (e.g.dinitrobenzoylphenylglycine) is also advantageous; a suitable eluant is,for example, a mixture of hexane/isopropanol/acetonitrile, e.g. in thevolume ratio 82:15:3.

Of course, it is also possible to obtain optically active compounds ofthe formula I according to the methods described above by using startingsubstances which are already optically active.

The invention further relates to the use of the compounds of the formulaI and/or their physiologically acceptable salts for the production ofpharmaceutical preparations, in particular in a non-chemical way. Inthis context, they can be brought into a suitable dose form togetherwith at least one solid, liquid and/or semiliquid excipient or auxiliaryand, if appropriate, in combination with one or more further activecompounds.

The invention further relates to pharmaceutical preparations comprisingat least one compound of the formula I and/or one of its physiologicallyacceptable salts.

These preparations can be used as medicaments in human or veterinarymedicine. Suitable vehicles are organic or inorganic substances whichare suitable for enteral (e.g. oral) or parenteral administration,topical application or for application in the form of an inhalationspray and do not react with the novel compounds, for example water,vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols,glycerol triacetate, gelatin, carbohydrates such as lactose or starch,magnesium stearate, talc and petroleum jelly. Tablets, pills, coatedtablets, capsules, powders, granules, syrups, juices or drops, inparticular, are used for oral administration, suppositories are used forrectal administration, solutions, preferably oily or aqueous solutions,in addition suspensions, emulsions or implants, are used for parenteraladministration, and ointments, creams or powders are used for topicalapplication. The novel compounds can also be lyophilized and thelyophilizates obtained used, for example, for the production ofinjection preparations. The preparations indicated can be sterilizedand/or can contain excipients such as lubricants, preservatives,stabilizers and/or wetting agents, emulsifiers, salts for affecting theosmotic pressure, buffer substances, colourants, flavourings and/or oneor more further active compounds, e.g. one or more vitamins.

For administration as an inhalation spray, sprays can be used whichcontain the active compound either dissolved or suspended in apropellant or propellant mixture (e.g. CO₂ or chlorofluorohydrocarbons).Expediently, the active compound is used here in micronized form, itbeing possible for one or more additional physiologically tolerablesolvents to be present, e.g. ethanol. Inhalation solutions can beadministered with the aid of customary inhalers.

The invention also relates to the use of the compounds of the formula Ias therapeutic active compounds.

The compounds of the formula I and their physiologically acceptablesalts can be used as integrin inhibitors in the control of diseases, inparticular of pathologically angiogenic disorders, thromboses, cardiacinfarct, coronary heart disorders, arteriosclerosis, tumours,inflammation and infections.

As a rule, the substances according to the invention can be administeredhere in analogy to other known, commercially available integrininhibitors, but in particular in analogy to the compounds described inU.S. Pat. No. 4,472,305, preferably in doses between approximately 0.05and 500 mg, in particular between 0.5 and 100 mg per dose unit. Thedaily dose is preferably between approximately 0.01 and 2 mg/kg of bodyweight. The specific dose for each patient depends, however, on allsorts of factors, for example on the efficacy of the specific compoundemployed, on the age, body weight, general state of health, sex, on thediet, on the time and route of administration, and on the excretionrate, pharmaceutical combination and severity of the particular disorderto which the therapy applies. Parenteral administration is preferred.

Above and below, all temperatures are indicated in °C. In the followingexamples, “customary working up” means: if necessary, water is added,the mixture is adjusted, if necessary, to a pH of between 2 and 10depending on the constitution of the final product, and extracted withethyl acetate or dichloromethane, and the organic phase is separatedoff, dried over sodium sulfate and evaporated, and the residue ispurified by chromatography on silica gel and/or by crystallization.

Mass spectrometry (MS): EI (electron impact ionization) M⁺ FAB (fastatom bombardment) (M+H)⁺

The R_(f) values indicated were determined by thin-layer chromatographyusing TLC films, silica gel 60 F₂₅₄.

EXAMPLE 1 Methyl8-[3-(pyridin-2-ylamino)propoxy]-6,11-dihydro-2H-dibenzo[cd,g]azulene-1-carboxylate

A solution of 3.5 g (0.011 mol) of ethyl(3-methoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)acetate in 50ml of 1N HCl and 80 ml of dioxane is stirred at room temperature for 16hours. After removal of the solvents, 3.0 g of(3-methoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)acetic acid(“AB”), R_(f) 0.68 (ethyl acetate) are obtained

A solution of 3.0 g of “AB” in 50 ml of thionyl chloride is treated witha few drops of DMF and stirred at 80° C. for 1 hour. After removal ofthe solvents, the residue is dissolved in 50 ml of dichloromethane,cooled to −10° and 1.61 g of aluminium chloride are added and themixture is subsequently stirred at room temperature for 2 hours. It isworked up in the customary manner and purified on silica gel 60(petroleum ether/ethyl acetate 4:1). 1.7 g of8-methoxy-1,6,11,11a-tetrahydrodibenzo[cd,g]azulen-2-one (“AC”), R_(f)0.51; EI 264 are obtained

0.64 g of NaH are added to a solution of 2.1 g of “AC” in 30 ml of THFunder an argon atmosphere. After stirring for 30 minutes, 3.4 ml ofdimethyl carbonate are added and the mixture is then subsequentlystirred for a further 4 hours. It is worked up in the customary manner,purified on silica gel 60 (petroleum ether/ethyl acetate 4:1) and 1.8 gof methyl8-methoxy-2-oxo-1,6,11,11a-tetrahydro-1H-dibenzo[cd,g]azulene-1-carboxylate(“AD”), R_(f) 0.40; EI 322 are obtained

9.3 g of ion exchanger Amberlite I and then 0.59 g of sodium borohydrideare added to a solution of 1.0 g of “AD” in 155 ml of THF. The mixtureis subsequently stirred at room temperature for 30 minutes. Afterremoval of the ion exchanger and solvent, methyl8-methoxy-2-hydroxy-1,6,11,11a-tetrahydro-1H-dibenzo-[cd,g]azulene-1-carboxylate(“AE”), R_(f) 0.69 (petroleum ether/ethyl acetate 1:1); EI 324 isobtained

A catalytic amount of DMAP is added to a solution of 0.3 g of “AE” in 18ml of dichloromethane and 0.14 ml of triethylamine. The mixture iscooled in an ice bath, 0.063 ml of methanesulfonyl chloride are addedand the mixture is subsequently stirred at room temperature for 14hours. After removal of the solvents, the residue is filtered throughsilica gel 60 (petroleum ether/ethyl acetate 5:1). After removal of thesolvents, the residue is dissolved in 50 ml of toluene, treated with0.179 g of DBU and stirred at 800 for 16 hours. After removal of thesolvent, the mixture is purified on silica gel 60 (petroleum ether/ethylacetate 9:1). 90 mg of methyl8-methoxy-6,11-dihydro-2H-dibenzo[cd,g]azulene-1-carboxylate (“AF”),R_(f) 0.68 (petroleum ether/ethyl acetate 4:1) are obtained

A suspension of 0.44 g of aluminium chloride and 0.26 g of ethanethiolis cooled in an ice bath. A solution of 0.2 g of “AF” in 5 ml ofdichloromethane is added. The mixture is stirred for 16 hours at roomtemperature, treated with 2N HCl and subsequently stirred. Aftercustomary working up, 181 mg of methyl8-hydroxy-6,11-dihydro-2H-dibenzo[cd,g]azulene-1-carboxylate (“AG”),R_(f) 0.368 (petroleum ether/ethyl acetate 4:1); EI 292 are obtained

A solution of 532 mg of 2-(3-hydroxypropylamino)-pyridine-N-oxide and540 mg of diethyl azodicarboxylate in 10 ml of DMF is added at roomtemperature under an argon atmosphere to a solution of 440 mg of “AG”and 866 mg of triphenylphosphine in 20 ml of DMG. The mixture issubsequently stirred for 3 days, the solvent is separated off and themixture is purified on silica gel 60 (ethyl acetate/methanol 9:1). 80 mgof methyl8-[3-(1-oxypyridin-2-ylamino)propoxy]-6,11-dihydro-2H-dibenzo[cd,g]azulene-1-carboxylate(“AH”), R_(f) 0.42 (ethyl acetate/methanol 4:1) are obtained

A solution of 80 mg of “AH” and 0.063 ml of phosphorus trichloride in 15ml of chloroform is heated under reflux for 3 hours. After customaryworking up, the residue is purified by means of preparative HPLC. 7.6 mgof methyl8-[3-(pyridin-2-ylamino)propoxy]-6,11-dihydro-2H-dibenzo[cd,g]azulene-1-carboxylate(“AI”), R_(f) 0.66 (ethyl acetate) are obtained

EXAMPLE 28-[3-(Pyridin-2-ylamino)propoxy]-6,11-dihydro-2H-dibenzo[cd,g]azulene-1-carboxylate

A solution of 7.6 mg of “AI” in 1.5 ml of dioxane is treated with 2.0 mlof 1N HCl and stirred at 110° for 16 hours. After removing the solvent,8-[3-(pyridin-2-ylamino)propoxy]-6,11-dihydro-2H-dibenzo[cd,g]azulene-1-carboxylicacid hydrochloride, R_(f) 0.62 (ethyl acetate/methanol 95:5+1% TEA) isobtained.

The compounds below are obtained analogously to Examples 1 and 2

8-[3-(1,4,5,6-tetrahydropyrimidin-2-ylamino)propoxy]-2,6,11,11a-tetrahydro-1H-dibenzo[cd,g]azulene-1-carboxylicacid

{8-[3-(1,4,5,6-tetrahydropyrimidin-2-ylamino)propoxy]-2,6,11,11a-tetrahydro-1H-dibenzo[cd,g]azulen-2-yl}-aceticacid

The following examples relate to pharmaceutical preparations:

EXAMPLE A

Injection Vials

A solution of 100 g of an active compound of the formula I and 5 g ofdisodium hydrogenphosphate is adjusted to pH 6.5 in 3 l ofdouble-distilled water using 2 N hydrochloric acid, sterile filtered,dispensed into injection vials, lyophilized under sterile conditions andaseptically sealed. Each injection vial contains 5 mg of activecompound.

EXAMPLE B

Suppositories

A mixture of 20 g of an active compound of the formula I is fused with100 g of soya lecithin and 1400 g of cocoa butter, poured into mouldsand allowed to cool. Each suppository contains 20 mg of active compound.

EXAMPLE C

Solution

A solution is prepared from 1 g of an active compound of the formula I,9.38 g of NaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄.12H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of double-distilled water. The solutionis adjusted to pH 6.8, made up to 1 l and sterilized by irradiation.This solution can be used in the form of eye drops.

EXAMPLE D

Ointment

500 mg of an active compound of the formula I are mixed with 99.5 g ofpetroleum jelly under aseptic conditions.

EXAMPLE E

Tablets

A mixture of 1 kg of active compound of the formula I, 4 kg of lactose,1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearateis compressed in a customary manner to give tablets such that eachtablet contains 10 mg of active compound.

EXAMPLE F

Coated Tablets

Tablets are pressed analogously to Example E and are then coated with acoating of sucrose, potato starch, talc, tragacanth and colourant in acustomary manner.

EXAMPLE G

Capsules

2 kg of active compound of the formula I are filled into hard gelatincapsules in a customary manner such that each capsule contains 20 mg ofthe active compound.

EXAMPLE H

Ampoules

A solution of 1 kg of active compound of the formula I in 60 l ofdouble-distilled water is sterile filtered, dispensed into ampoules,lyophilized under sterile conditions and aseptically sealed. Eachampoule contains 10 mg of active compound.

EXAMPLE I

Inhalation Spray

14 g of active compound of the formula I are dissolved in 10 l ofisotonic NaCl solution and the solution is filled into commerciallyavailable spray containers having a pump mechanism. The solution can besprayed into the mouth or nose. One burst of spray (approximately 0.1ml) corresponds to a dose of approximately 0.14 mg.

What is claimed is:
 1. Compounds of the formula I

in which R¹ is OR₄, NHR⁴ or NA″₂, R² is H, Hal, NO₂, NHR⁴, NA″₂, OR⁴,SO₃R⁴, SO₂R⁴ or SR⁴, R³ is NH₂, H₂N—C(═NH) or H₂N—(C═NH)—NH, where theprimary amino groups are optionally protected with an amino protectivegroup or R⁵—NH—, R⁴ is H, A, Ar, or Aralk, R⁵ is a mono- or binuclearheterocycle having 1 to 4 N, O and/or S atoms, which can beunsubstituted or mono-, di- or trisubstituted by Hal, A″, —CO—A, OA′,CN, COOA′, CONH₂, NO₂, ═NH or ═O, A is alkyl having 1-15 C atoms orcycloalkyl having 3-15 C atoms, which is unsubstituted or mono-, di- ortrisubstituted by R⁶, and in which one, two or three methylene groupscan be replaced by N, O and/or S, R⁶ is Hal, NO₂, NHA′, NA″₂, OA′,phenoxy, CO—A′, SO₃A′, CN, NHCOA′, COOA′, CONA′₂, or SO₂A′, A′ is H oralkyl having 1-6 C atoms, A″ is alkyl having 1-6 C atoms, Ar is a mono-or binuclear aromatic ring system, which is unsubstituted or mono-, di-or trisubstituted by alkyl having 1-6 C atoms and/or an R⁶-substitutedmono- or binuclear aromatic ring system having 0, 1, 2, 3 or 4 N, Oand/or S atoms, Aralk is a aralkylene having 7-14 C atoms, which isunsubstituted or mono-, di- or trisubstituted by R⁶ and in which one,two or three methylene groups can be replaced by N, O and/or S, Hal isF, Cl, Br, or I, m, n in each case independently of one another are 0,1, 2, 3, or 4, and their physiologically acceptable salts and solvates.2. Enantiomers or diastereomers of the compounds of the formula Iaccording to claim
 1. 3. Compounds of the formula I according to claim 1a) 8-[3-(pyridin-2-ylamino)propoxy]-6,11-dihydro-2H-dibenzo[cd,g]azulene-1-carboxylic acid; b)8-[3-(1,4,5,6-tetrahydropyrimidin-2-ylamino)propoxy]-2,6,11,11a-tetrahydro-1H-dibenzo[cd,g]azulene-1-carboxylicacid; c){8-[3-(1,4,5,6-tetrahydropyrimidin-2-ylamino)propoxy]-2,6,11,11a-tetrahydro-1H-dibenzo[cd,g]azulene-2-yl}aceticacid; and their physiologically acceptable salts and solvates. 4.Process for the preparation of compounds of the formula I according toclaim 1, and of their salts and solvates, characterized in that a) acompound of the formula I is set free from one of its functionalderivatives by treating with a solvolysing or hydrogenolysing agent, orb) a radical R¹, R², and/or R³ is converted into another radical, R¹,R², and/or R³ by, i) converting an amino group into a guanidino group byreaction with an amidinating agent, ii) hydrolysing an ester, iii)reducing a carboxylic acid to an alcohol, or iv) converting ahydroxyamidine into an amidine by hydrogenation or c) a base or acid ofthe formula I is converted into one of its salts.
 5. Compounds of theformula I according to claim 1 and their physiologically acceptablesalts and solvates as GPIIb/IIIa antagonists for the control ofthromboses, cardiac infarct, coronary heart disorders andarteriosclerosis.
 6. Compounds of the formula I according to claim 1 andtheir physiologically acceptable salts and solvates as α_(v) integrininhibitors for the control of pathologically angiogenic disorders,thromboses, cardiac infarct, coronary heart disorders, arteriosclerosis,tumours, osteoporosis and rheumatoid arthritis.
 7. A pharmaceuticalcomposition characterized in that it contains at least one compound ofthe formula I according to claim 1 and/or one of its physiologicallyacceptable salts or solvates.
 8. A process for the production of apharmaceutical composition characterized in that a compound of formula Iaccording to claim 1 and/or one of its physiologically acceptable saltsor solvates is brought into a suitable dose form together with at leastone solid, liquid or semi-liquid vehicle or excipient.
 9. A method fortreatment of a disease or condition affected by α_(v) integrininhibition which comprises administering an α_(v) integrin inhibitioneffective amount of a compound of the formula I of claim 1 orphysiologically acceptable salt or solvate thereof.
 10. The method ofclaim 9, wherein the disease or condition is cancer, a tumor-inducedangiogenic disease, oncoses, osteoporosis, an osteolytic disorder,angiogenesis, thromboses, cardiac infarct, coronary heart disorder,arteriosclerosis or rheumatoid arthritis.
 11. Compounds of claim 1,wherein: Aralk is benzyl or phenethyl, A is methyl, ethyl, propyl,isopropyl, butyl or tert-butyl, Ar is unsubstituted or mono-substitutedphenyl, and R⁵ is 1H-imidazol-2-yl, 4,5-dihydro-1H-imidazol-2-yl,5-oxo-4,5-dihydro-1H-imidazol-2-yl, thiazol-2-yl, 1H-benzimidazol-2-yl,2H-pyrazol-2-yl, 1H-tetrazol-5-yl, 2-imino-imidazolin-4-on-5-yl,1-alkyl-1,5-dihydroimidazol-4-on-2-yl, pyridin-2-yl, pyrimidin-2-yl or1,4,5,6-tetrahydro-pyrimidin-2-yl.
 12. Compounds of claim 1, wherein R²is H.
 13. Compounds of claim 1, wherein R² is H, R¹ is OR⁴ and R⁴ is Hor A.
 14. Compounds of claim 1, wherein R² is H, R¹ is OR⁴, R⁴ is H or Aand R³ is H₂N—C(═NH), H₂N—(C═NH)—NH, 1H-imidazol-2-ylamino,4,5dihydro-1H-imidazol-2-ylamino,5-oxo-4,5-dihydro-1H-imidazol-2-ylamino, 1H-benzimidazol-2-ylamino,2H-pyrazol-2-ylamino, 1-methyl-1,5-dihydroimidazol-4-on-2-yl-amino,pyridin-2-ylamino, pyrimidin-2-ylamino or1,4,5,6-tetrahydro-pyrimidin-2-ylamino.
 15. Compounds of claim 1,wherein m is 0 or
 1. 16. Compounds of claim 1, wherein m is 0 or 1 andR² is H.
 17. Compounds of claim 1, wherein R² is H; R¹ is OR⁴, R⁴ is Hor A and m is 0 or
 1. 18. Compounds of claim 1, wherein R² is H, R¹ isOR⁴, R⁴ is H or A and A is methyl, ethyl, propyl, isopropyl, butyl ortert-butyl and m is 0 or
 1. 19. Compounds of claim 1, wherein R² is H,R¹ is OR⁴, R⁴ is H or A, A is methyl, ethyl, propyl, isopropyl, butyl ortert-butyl, R³ is H₂N—C(═NH), H₂N—(C═NH), H₂N—(C═NH)—NH,1H-imidazol-2-ylamino, 4,5dihydro-1H-imidazol-2-ylamino,5-oxo4,5-dihydro-1H-imidazol-2-ylamino, 1H-benzimidazol-2-ylamino,2H-pyrazol-2-ylamino, 2-iminoimidazolidin-4-on-5-ylamino,1-methyl-1,5-dihydroimidazol-4-on-2-ylamino, pyridin-2-ylamino,pyrimidin-2-ylamino or 1,4,5,6,-tetrahydropyrimidin-2-ylamino; m is 0 or1 and n is 2, 3 or
 4. 20. Compounds of claim 1, wherein the aminoprotective group, if present, is an unsubstituted or substituted acyl,aralkoxymethyl or aralkyl group.
 21. Compounds of claim 20, wherein theamino protective group, if present, is BOC, Mtr, CBZ, Fmoc, benzyl oracetyl.